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系統識別號 U0007-1805200916334300
論文名稱(中文) Dipyridamole對抗腎臟發炎與缺氧作用之研究
論文名稱(英文) The Effects of Dipyridamole on Renal Inflammation and Hypoxia
校院名稱 臺北醫學大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Graduate Institute of Clinical Medicine
學年度 97
學期 2
出版年 98
研究生(中文) 陳作孝
研究生(英文) Tso-Hsiao Chen
學號 D102091012
學位類別 博士
語文別 中文
口試日期 2009-05-07
論文頁數 99頁
口試委員 指導教授-陳保羅
共同指導教授-李宏謨
委員-樓迎統
委員-陳振文
委員-林裕峯
委員-陳漢湘
中文關鍵字 Dipyridamole, 血红  素氧合酶  1, 分裂素蛋白激酶  磷酸酶  1, 骨橋素 
英文關鍵字 Dipyridamole, Heme oxygenase-1, Mitogen-activated kinase phosphatase-1, Osteopontin 
學科別分類
中文摘要 研究背景. 慢性腎臟病的病理特徵包括腎絲球硬化、腎間質白血球浸潤、腎小管間質纖維化、腎絲球及腎小管周邊微血管喪失。任何形式的腎臟損傷會造成發炎物質的生成,微血管喪失引起組織的缺氧缺血,產生反應性氧族(ROS),進一步強化發炎反應、組織的修補和纖維化。腎臟慢性的缺氧會活化腎素-血管收縮素系統,局部的血管收縮素II增加會引起氧化壓力。同時,腎臟組織的缺氧缺血反應會增加血红素氧合酶1的表現,提供腎臟損傷的保護機制。Dipyridamole是一個核苷運送的抑制劑,也是一個非選擇性磷酸二酯酶(phosphodiesterase)的抑制劑。Dipyridamole應用在腎臟病治療可改善蛋白尿,然而,作用的機轉並不清楚。本研究將探討dipyridamole 抗發炎及抗氧化的作用,並研究活化分裂素蛋白激酶磷酸酶1 (MKP-1)及血红素氧合酶1 (HO-1)扮演的角色。
研究方法. 白細胞介素6 (interleukin 6, 簡稱IL-6)、單核球趨化蛋白-1 (monocyte chemoattractant protein, 簡稱MCP-1)及骨橋素(osteopontin, 簡稱OPN) 以ELISA方法測量。ROS的產量以(DCF)螢光強度測量。研究PI-3K-PKB/Akt,分裂素蛋白激酶(MAPK) 和NF-kB 訊息傳遞路徑。利用分裂素蛋白激酶磷酸酶1和血红素氧合酶1的短鏈干擾核糖核酸(siRNA)轉殖的細胞,抑制MKP-1及 HO-1基因表現,來研究dipyridamole的分子作用機制。
結果. 在大鼠腎膈細胞(RMCs),加入100nM的血管收縮素II會增加ROS的產生,PI-3K的抑制劑 Ly294001及wortmannin會阻斷血管收縮素II所誘導HIF-1α堆積,顯示血管收縮素II是透過ROS依賴的PI-3K-PKB /Akt 路徑,誘導HIF-1α堆積。在大鼠巨噬細胞(RAW 264.7 cells),dipyridamole可以活化MKP-1,以MKP-1 siRNA轉殖技術抑制MKP-1基因表現或加入MKP-1的抑制劑 triptolide,可以抑制脂多醣體(lipopolysaccharide,LPS)在巨噬細胞所誘導環氧化酵素2 (COX-2)的表現。在大鼠腎膈細胞,我們同樣發現dipyridamole可以抑制脂多醣體所誘導IL-6和MCP-1分泌,ROS的產量有明顯的減少且和dipyridamole劑量相關。另外,dipyridamole會抑制脂多醣體引起的NF-kB和脫氧核醣核酸結合能力及IkB的磷酸化。以MKP-1 siRNA轉殖的大鼠腎膈細胞則會降低dipyridamole對脂多醣體所誘導IL-6表現的抑制作用。ERK 1/2 及p38MAPK 路徑也參與了脂多醣體所引發的MCP-1和COX-2的表現,可以受到dipyridamole及抗氧化劑 l-NAC所抑制。然而,以SnPP (HO-1抑制劑)前處理RMC細胞,可逆轉dipyridamole對ROS及發炎反應的抑制作用。在大鼠腎小管上皮細胞(NRK-52E),加入化學缺氧劑氯化鈷(CoCl2),會增加OPN蛋白質表現增加。Dipyridamole可以誘導HO-1的表現增加與抑制CoCl2所誘導OPN的分泌,以SnPP或血色素(一氧化碳去除劑),可逆轉dipyridamole對OPN的抑制作用,顯示HO-1與dipyridamole抑制CoCl2誘導OPN的表現有關。以HO-1 siRNA轉殖的NRK-52E細胞會降低dipyridamole所誘導MKP-1的磷酸化及活化,而以MKP-1 siRNA轉殖的NRK-52E細胞會則能逆轉dipyridamole對OPN的抑制作用。
結論. 我們的實驗結果顯示,dipyridamole會先藉由活化MKP-1的方式使得p38 MAPK去磷酸化而失去功能。此外,血管收縮素II透過ROS依賴的路徑來誘導HIF-1α堆積。在大鼠腎膈細胞,dipyridamole藉由HO-1降低ROS ,抑制脂多醣體所誘導COX-2表現及MCP-1分泌。在NRK-52E細胞,dipyridamole會經由誘導HO-1及MKP-1的活化,降低CoCl2所誘導OPN的分泌。總而言之, dipyridamole可能透過抗發炎及抗氧化的作用,提供在慢性腎臟病治療的好處。
英文摘要 Background. Chronic kidney disease is characterized by glomerulosclerosis, interstitial leukocyte infiltration, tubulointerstitial fibrosis, and loss of glomerular and peritubular capillaries. Renal injury of any kind generates mediators of inflammation. Hypoxia/ischemia secondary to loss of capillaries also contributes to reactive oxygen species (ROS) generation and may further enhance the inflammatory process, tissue remodeling and fibrosis. Chronic hypoxia can activate the renin-angiotensin system (RAS) and local angiotensin II induces oxidative stress. In the meantime, up-regulation of heme ogygenase-1 (HO-1) provides protection against renal injury that follows hypoxia/ischemia. Dipyridamole is a nucleoside transport inhibitor and a non-selective phosphodiesterase inhibitor, which has been shown to improve proteinuria. However, the mechanisms by which dipyridamole exerts its beneficial effects on renal disease are not completely understood. In the present study, we investigated the roles of mitogen-activated kinase phosphatase-1 (MKP-1) and HO-1 in dipyridamole's anti-inflammatory and anti-oxidative effects.
Methods. IL-6, MCP-1 and OPN secretions were measured by ELISA kits. ROS generation was measured using the fluorescent probe 2',7'- dichlorofluorescein (DCF). PI-3K-PKB/Akt, MAPK and NF-kB signal pathways were studied. HO-1 and MKP-1 siRNA were used for gene knockdown to investigate the molecular mechanisms of dipyridamole.
Results. Treatment of rat mesangial cells (RMCs) with Ang II (100 nM) increased production of ROS. Ang II-stimulated HIF-1alpha accumulation was blocked by the phosphatidylinositol 3-kinase (PI-3K) inhibitors, Ly 294001, and wortmannin, suggesting that Ang II may stimulate a ROS-dependent activation of the PI-3K-PKB/Akt pathway, which leads to HIF-1alpha accumulation. In RAW 264.7 cells, dipyridamole stimulated transient activation of MKP-1, a potent inhibitor of p38 MAPK function. Knockdown of MKP-1 by transfecting MKP-1 siRNA or inhibition of MKP-1 by the specific inhibitor, triptolide, significantly reduced the inhibitory effects of dipyridamole on COX-2 expression induced by LPS. We also showed that dipyridamole inhibited LPS-induced IL-6 and MCP-1 secretion in RMCs. Pretreated with dipyridamole showed significantly inhibition of ROS generation in a dose-dependent manner. In addition, dipyridamole inhibited the LPS-stimulated NF-kB DNA binding activity and IkB phosphorylation. The dipyridamole inhibitory effect on LPS-induced IL-6 secretion was reduced in MKP-1 siRNA knockdown cells. ERK1/2 and p38 MAPK signaling pathways were demonstrated to be involved in the LPS-induced MCP-1 secretion and COX-2 expression, and were inhibited by dipyridamole and l-NAC treatment. However, pretreatment of RMCs with tin protoporphyrin (Snpp; an HO-1 inhibitor) reversed the inhibitory effect of dipyridamole on ROS and inflammatory responses. Incubation of rat renal tubular NRK52E cells with cobalt chloride (CoCl2) increased OPN production. Dipyridamole could induce HO-1 expression and inhibited CoCl2-induced OPN secretion. Pretreatment of cells with Snpp, or hemoglobin (a CO-scavenging agent), reversed the inhibition of OPN expression by dipyridamole. Transfection of HO-1 siRNA reduced dipyridamole-stimulated MKP-1 phosphorylation. Knockdown of MKP-1 reversed the inhibition of OPN expression by dipyridamole.
Conclusions. Our results demonstrate that dipyridamole may exert its anti-inflammatory effect via activation of MKP-1, which dephosphorylates and inactivates p38 MAPK. In addition, Ang II increases ROS-dependent HIF-1 alpha accumulation. Dipyridamole inhibits the expression of COX-2 and secreted MCP-1 in LPS-treated RMCs via HO-1-mediated ROS reduction. In NRK-52E cells, dipyridamole may suppress CoCl2-induced OPN secretion via induction of HO-1 and activation of MKP-1. Taken together, these data suggest that dipyridamole may contribute to its beneficial effects on chronic kidney disease through its anti-inflammatory and anti-oxidative effects.
論文目次 縮寫表 (Abbreviations) ------------------------------- iv
圖目錄 (Figures Contents) ---------------------------- vi
中文摘要 (Abstract in Chinese) ----------------------- ix
英文摘要 (Abstract in English) ---------------------- xii
第一章 緒論 (Introduction)
第一節 慢性腎臟病的病理變化與臨床重要性--------------- 1
第二節 Dipyridamole的藥理作用與臨床應用--------------- 4
第三節 分裂素活化蛋白激酶磷酸酶1 (MKP-1) ------------ 6
第四節 低氧症可誘導因素1 (HIF-1) -------------------- 7
第五節 血红素氧合酶1 (HO-1) -------------------------- 8
第六節 骨橋素 ---------------------------------------- 9
第七節 研究目的 ------------------------------------- 10
第二章 研究方法與材料 (Materials and Methods) -------- 11
第三章 研究結果 (Results)
第一節 血管收縮素II在大鼠腎膈細胞誘導HIF-1α堆積 ------ 19
第二節 Dipyridamole經由活化MKP-1抑制脂多醣體在巨噬細胞 所誘導環氧化酵素2的表現 ------------------------------ 21
第三節 Dipyridamole經由活化MKP-1抑制脂多醣在大鼠腎膈細胞 所誘導白細胞介素6的表現 ------------------------------ 25
第四節 Dipyridamole經由HO-1降低反應性氧族抑制脂多醣體在 大鼠腎膈細胞所誘導環氧化酵素2及單核細胞趨化素1的表現-- 27
第五節 Dipyridamole經由HO-1抑制大鼠腎小管上皮細胞骨橋素 的表現 ----------------------------------------------- 31
第四章 討論 (Discussion)
第一節 血管收縮素II在大鼠腎膈細胞誘導HIF-1α堆積 ------ 35
第二節 Dipyridamole經由活化MKP-1抑制脂多醣體 在巨噬細胞所誘導環氧化酵素2的表現 -------------------- 38
第三節 Dipyridamole經由活化MKP-1抑制脂多醣在大鼠腎膈細胞 所誘導白細胞介素6的表現 ------------------------------ 43
第四節 Dipyridamole經由HO-1降低反應性氧族抑制脂多醣體在 大鼠腎膈細胞所誘導環氧化酵素2及單核細胞趨化素1的表現 - 46
第五節 Dipyridamole經由HO-1抑制大鼠腎小管上皮細胞骨橋素 的表現 ----------------------------------------------- 50
第五章 結論與展望 (Conclusion and Perspective) ------- 55 參考文獻 (References) ------------------------------- 57
圖表 (Tables and Figures) ---------------------------- 74
參考文獻 Abbot, F., Ryan, J.J., Ceska, M., Matsushima, K., Sarra, C.E., Rees, A.J., 1991. Interleukin-1 beta stimulates human mesangial cells to synthesize and release interleukin-6 and -8. Kidney Int 40:597-605
Aiello, L.P., 2000. Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int 77: S113–S119
Alvarez-Maqueda, M., El Bekay, R., Alba, G., Monteseirin, J., Chacon, P., Vega, A., Martin-Nieto, J., Bedoya, F.J., Pintado, E., Sobrino, F., 2004. 15-deoxy-delta 12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in a reactive oxygen species-dependent manner in human lymphocytes. J Biol Chem 279: 21929-21937
Ardyanto, T.D., Osaki, M., Tokuyasu, N., Nagahama, Y., Ito, H., 2006. CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway. Int J Oncol 29: 549-555
Ashkar, S., Weber, G.F., Panoutsakopoulou, V., Sanchirico, M.E., Jansson, M., Zawaideh, S., Rittling, S.R., Denhardt, D.T., Glimcher, M.J., Cantor, H., 2000. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287: 860-864
Awazu, M., Omori, S., Hida, M., 2002. MAP kinase in renal development. Nephrol Dial Transplant 17(Suppl 9):5-7
Baldwin, A.S., 1996. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649-656
Basile, D.P., Fredrich, K., Alausa, M., Vio, C.P., Liang, M., Rieder, M.R., Greene, A.S., Cowley, A.W., Jr., 2005. Identification of persistently altered gene expression in the kidney after functional recovery from ischemic acute renal failure. Am J Physiol Renal Physiol 288: F953-963
Beavo, J.A., 1995. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 75:725-732
Bender, A.T., Beavo, J.A., 2006. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58: 488-520
Bielekova, B., Lincoln, A., McFarland, H., Martin, R., 2000. Therapeutic potential of phosphodiesterase-4 and -3 inhibitors in Th1-mediated autoimmune diseases. J Immunol 164:1117-1130
Bowie, A., O'Neill, L.A., 2000. Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59:13-20
Brown, K., Gerstberger, S., Carlson, L., Franzoso, G., Siebenlist, U., 1995. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485-1492
Burnouf, C., Pruniaux, M.P., 2002. Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr Pharm Des 8:1255-1265
Camara, S., Cruz, J.P., Frutos, M.A., Sanchez, P., Lopez de Novales, E., Sanchez, E., Sanchez de la Cuesta, F., 1991. Effects of dipyridamole on the short-term evolution of glomerulonephritis. Nephron 58: 13-16
Camhi, S.L., Alam, J., Otterbein, L., Sylvester, S.L., Choi, A.M., 1995. Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation. Am J Respir Cell Mol Biol 13: 387-398
Chandel, N.S., McClintock, D.S., Feliciano, C.E., Wood, T.M., Melendez, J.A., Rodriguez, A.M., Schumacker, P.T., 2000. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275: 25130-25138
Chandel, N.S., 2000. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia. J Biol Chem 275: 25130–25138
Chakrabarti, S., Vitseva, O., Iyu, D., Varghese, S., Freedman, J.E., 2005. The effect of dipyridamole on vascular cell-derived reactive oxygen species. J Pharmacol Exp Ther 315: 494–500
Chen, T.H., Kao, Y.C., Chen, B.C., Chen, C.H., Chan, P., Lee, H.M., 2006. Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. Eur J Pharmacol 541: 138-146
Chen, Z., Hagler, J., Palombella, V.J., 1995. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 9:1586-1595
Chen, P., Li, J., Barnes, J., Kokkonen, G.C., Lee, J.C., Liu, Y., 2002. Restraint of proinflammatory cytokine biosynthesis by mitogen- activated protein kinase phosphatase-1 in lipopolysaccharide- stimulated macrophages. J Immunol 169:6408-6418
Cheng, J., Grande, J.P., 2007. Cyclic nucleotide phosphodiesterase (PDE) inhibitors: novel therapeutic agents for progressive renal disease. Exp Biol Med (Maywood) 232: 38-51
Choi, A.M., Alam, J., 1996. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15: 9-19
Choi, J.S., Kim, H.Y., Cha, J.H., Choi, J.Y., Lee, M.Y., 2007. Transient microglial and prolonged astroglial upregulation of osteopontin following transient forebrain ischemia in rats. Brain Res 1151: 195-202
Coleman, D., Ruef, C., 1992. Interleukin-6: An autocrine regulator of mesangial cell growth. Kidney Int 41: 604–611
Cuturi, M.C., Christoph, F., Woo, J., Iyer, S., Brouard, S., Heslan, J.M., Pignon, P., Soulillou, J.P., Buelow, R. 1999. RDP1258, a new rationally designed immunosuppressive peptide, prolongs allograft survival in rats: analysis of its mechanism of action. Mol Med 5: 820-832
Dastidar, S.G., Rajagopal, D., Ray, A., 2007. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs 8: 364-372
Denhardt, D.T., Guo, X., 1993. Osteopontin: a protein with diverse functions. FASEB J 7: 1475-1482
Dubey, R.K., Gillespie, D.G., Jackson, E.K., 1999. Adenosine inhibits collagen and total protein synthesis in vascular smooth muscle cells. Hypertension 33: 190-194
Eddy, A.A., 1994. Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions. J Am Soc Nephrol 5: 1273–1287
Eddy, A.A., 2005. Progression in Chronic Kidney Disease. Advances in Chronic Kidney Disease 12:353-365
Enomoto, N., 2002. Hypoxic induction of hypoxia-inducible factor-1α and oxygen-regulated gene expression in mitochondrial DNA-depleted HeLa cells. Biochem Biophys Res Commun 297: 346–352
Endo, Y., Kanbayashi, H., Hara, M., 1993. Experimental immunoglobulin A nephropathy induced by gram-negative bacteria. Nephron 65: 196–205
Gaedeke, J., Noble, N.A., Border, W.A., 2005. Curcumin blocks fibrosis in anti-Thy 1 glomerulonephritis through up-regulation of heme oxygenase 1. Kidney Int 68: 2042-2049
Gaitanaki, C., Kalpachidou, T., Aggeli, I.K., Papazafiri, P., Beis, I., 2007. CoCl2 induces protective events via the p38-MAPK signalling pathway and ANP in the perfused amphibian heart. J Exp Biol 210: 2267-2277
Giachelli, C.M., Pichler, R., Lombardi, D., Denhardt, D.T., Alpers, C.E., Schwartz, S.M., Johnson, R.J., 1994. Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. Kidney Int 45: 515-524
Gloire, G., Legrand-Poels, S., Piette, J., 2006. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72: 1493-1505
Gomez, G.C., Lopez, M.J., Gonzalez, E., Egido, J., 1994. Soluble IgA and IgG aggregates are catabolized by cultured rat mesangial and induce production of TNF- and IL-6 and proliferation. J Immunol 154: 5247–5256
Graf, K., Stawowy, P., 2004. Osteopontin: a protective mediator of cardiac fibrosis? Hypertension 44: 809-810
Granholm, N.A., Cavallo, T., 1994. Long-lasting effects of bacterial lipopolysaccharide promote progression of lupus nephritis in NZB/W mice. Lupus 3: 507–514
Hammond, J.R., Williams, E.F., Clanachan, A.S., 1985. Affinity of calcium channel inhibitors, benzodiazepines, and other vasoactive compounds for the nucleoside transport system. Can J Physiol Pharmacol 63: 1302-1307
Hammond, J.R., Stolk, M., Archer, R.G., McConnell, K., 2004. Pharmacological analysis and molecular cloning of the canine equilibrative nucleoside transporter 1. Eur J Pharmacol 491: 9-19
Harmankaya, O., Basturk, T., Ozturk, Y., Karabiber, N., Obek, A., 2001. Effect of acetylsalicylic acid and dipyridamole in primary membranoproliferative glomerulonephritis type I. Int Urol Nephrol 33: 583-587
Haas, C.S., Schocklmann, H.O., Lang, S., Kralewski, M., Sterzel, R.M., 1999. Regulatory mechanism in glomerular mesangial cell proliferation. J Nephrol 12: 405-15
Haas, C., Car, B., Ryffel, B.E., Hir, M., 1996. Lipopolysaccharide-induced glomerulonephritis develops in the absence of interferon-gamma signaling. Exp Nephrol 64: 222–230
Maxwell. P., 2003. HIF-1: An ogygen response system with specialy relevance to th kidney. J Am Soc Nephrol 14:2712-2722

Hewitson, T.D., Tait, M.G., Kelynack, K.J., Martic, M., Becker, G.J., 2002. Dipyridamole inhibits in vitro renal fibroblast proliferation and collagen synthesis. J Lab Clin Med 140: 199-208
Higgins, D.F., Biju. M.P., Akai, Y., Wutz, A., Johnson, R.S., Haase, V.H., 2004. Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physio 287(6):F1223-32
Hung, K.Y., Chen, C.T., Huang, J.W., Lee, P.H., Tsai, T.J., Hsieh, B.S., 2001. Dipyridamole inhibits TGF-beta-induced collagen gene expression in human peritoneal mesothelial cells. Kidney Int 60: 1249-1257
Hung, K.Y., Chen, C.T., Yen, C.J., Lee, P.H., Tsai, T.J., Hsieh, B.S., 2001. Dipyridamole inhibits PDGF-stimulated human peritoneal mesothelial cell proliferation. Kidney Int 60: 872-881
Hung, K.Y., Shyu, R.S., Fang, C.C., Tsai, C.C., Lee, P.H., Tsai, T.J., Hsieh, B.S., 2001c. Dipyridamole inhibits human peritoneal mesothelial cell proliferation in vitro and attenuates rat peritoneal fibrosis in vivo. Kidney Int 59: 2316-2324
Huang, L.E., 2002. Leu-574 of HIF-1α is essential for the von Hippel-Lindau (VHL)-mediated degradation pathway. J Biol Chem 277: 41750–41755
Iguchi, S., Nishi, S., Ikegame, M., Hoshi, K., Yoshizawa, T., Kawashima, H., Arakawa, M., Ozawa, H., Gejyo, F., 2004. Expression of osteopontin in cisplatin-induced tubular injury. Nephron Exp Nephrol 97: e96-105


Ikeda, M., Ikeda, U., Ohkawa, F., Shimada, K., Kano, S., 1994. Nitric oxide synthesis in rat mesangial cells induced by cytokines. Cytokine 6: 602-607
Iuliano, L., Pedersen, J.Z., Rotilio, G., Ferro, D., Violi, F., 1995. A potent chain-breaking antioxidant activity of the cardiovascular drug dipyridamole. Free Radic Biol Med 18: 239–247
Iuliano, L., Colavita, A.R., Camastra, C., Bello, V., Quintarelli, C., Alessandroni, M., Piovella, F., Violi, F., 1996. Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole. Br J Pharmacol 119: 1438–1446
Jin, H.O., An, S., Lee, H.C., Woo, S.H., Seo, S.K., Choe, T.B., Yoo, D.H., Lee, S.B., Um, H.D., Lee, S.J., Park, M.J., Kim, J.I., Hong, S.I., Rhee, C.H., Park, I.C., 2007. Hypoxic condition- and high cell density-induced expression of Redd1 is regulated by activation of hypoxia-inducible factor-1alpha and Sp1 through the phosphatidylinositol 3-kinase/Akt signaling pathway. Cell Signal 19: 1393-1403
Karkar, A.M., Rees, A.J., 1997. Influence of endotoxin contamination on anti-GBM antibody induced glomerular injury in rats. Kidney Int 52: 1579–1583
Khanna, A., Plummer, M., Bromberek, C., Bresnahan, B., Hariharan, S., 2002. Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity. Kidney Int 62: 2257-2263
Kitamura, Y., Matsuoka, Y., Nomura, Y., Taniguchi, T., 1998. Induction of inducible nitric oxide synthase and heme oxygenase-1 in rat glial cells. Life Sci 62: 1717-1721
Kim, S., 2000. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol. Rev 52: 11–34
Komers, R., Epstein, M., 2002. Cyclooxygenase-2 expression and function in renal pathophysiology. J Hypertens 20: S11-15
Kossmehl, P., Schonberger, J., Shakibaei, M., Faramarzi, S., Kurth, E., Habighorst, B., von Bauer, R., Wehland, M., Kreutz, R., Infanger, M., Schulze-Tanzil, G., Paul, M., Grimm, D., 2005. Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion. J Mol Med 83: 626-637
Kramer, A.B., Ricardo, S.D., Kelly, D.J., Waanders, F., van Goor, H., Navis, G., 2005. Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis. J Pathol 207: 483-492
Kusmic, C., Picano, E., Busceti, C.L., Petersen, C., Barsacchi, R., 2000. The antioxidant drug dipyridamole spares the vitamin E and thiols in red blood cells after oxidative stress. Cardiovasc Res 47: 510–514
Lan, H.Y., Yu, X.Q., Yang, N., Nikolic-Paterson, D.J., Mu, W., Pichler, R., Johnson, R.J., Atkins, R.C., 1998. De novo glomerular osteopontin expression in rat crescentic glomerulonephritis. Kidney Int 53: 136-145
Levin, A., 1999.Management of membranoproliferative glomerulonephritis: evidence-based recommendations. Kidney Int 70: S41-46
Leonard, M., Ryan, M.P., Watson, A.J., Schramek, H., Healy, E., 1999. Role of MAP kinase pathways in mediating IL-6 production in human primary mesangial and proximal tubular cells. Kidney Int 56(4): 1366-1377
Li, X.Y., Zhang, C., Wang, S.F., Ji, Y.L., Wang, H., Zhao, L., Xu, D.X., 2008. Maternally administered lipopolysaccharide (LPS) upregulates the expression of heme oxygenase-1 in fetal liver: The role of reactive oxygen species. Toxicol Lett 176: 169-177
Li, C., Sun, B.K., Lim, S.W., Song, J.C., Kang, S.W., Kim, Y.S., Kang, D.H., Cha,J.H., Kim,J., Yang,C.W., 2005. Combined effects of losartan and pravastatin on interstitial inflammation and fibrosis in chronic cyclosporine-induced nephropathy. Transplantation 79: 1522-1529
Liaw, L., Lindner, V., Schwartz, S.M., Chambers, A.F., Giachelli, C.M., 1995. Osteopontin and beta 3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp- dependent endothelial migration in vitro. Circ Res 77: 665-672
Loboda, A., Jazwa, A., Wegiel, B., Jozkowicz, A., Dulak, J., 2005. Heme oxygenase-1-dependent and -independent regulation of angiogenic genes expression: effect of cobalt protoporphyrin and cobalt chloride on VEGF and IL-8 synthesis in human microvascular endothelial cells. Cell Mol Biol 51: 347-355
Lorena, D., Darby, I.A., Gadeau, A.P., Leen, L.L., Rittling, S., Porto, L.C., Rosenbaum, J., Desmouliere, A., 2006. Osteopontin expression in normal and fibrotic liver. altered liver healing in osteopontin-deficient mice. J Hepatol 44: 383-390
Lu, N., Zhou, H., Lin, Y.H., Chen, Z.Q., Pan, Y., Li, X.J., 2007. Oxidative stress mediates CoCl(2)-induced prostate tumour cell adhesion: role of protein kinase C and p38 MAPK. Basic Clin Pharmacol Toxicol 101: 41-46
Marieke, E.A., Fokko, W., Willeke, M.S., Leendert, E., Mohamed, R.D., 1993. Soluble aggregates of IgG and immune complexes enhance IL-6 production by renal mesangial cells. Kidney Int 43: 544–553
Marina, L., Sonya, M., Christine, B., Jeremy, S., Andrew, R.C., 2002. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol 22:7802-7811
Maines, M.D., Mayer, R.D., Ewing, J.F., McCoubrey, W.K., 1993. Induction of kidney heme oxygenase-1 (HSP32) mRNA and protein by ischemia/reperfusion: possible role of heme as both promotor of tissue damage and regulator of HSP32. J Pharmacol Exp Ther 264: 457-462
Malyankar, U.M., Almeida, M., Johnson, R.J., Pichler, R.H., Giachelli, C.M., 1997. Osteopontin regulation in cultured rat renal epithelial cells. Kidney Int 51: 1766-1773
Mark, A., Hock, T., Kapturczak, M.H., Agarwal, A., Hill-Kapturczak, N., 2005. Induction of heme oxygenase-1 modulates the profibrotic effects of transforming growth factor-beta in human renal tubular epithelial cells. Cell Mol Biol 51: 357-362
Montellano, P.R., 2000. The mechanism of heme oxygenase. Curr Opin Chem Biol 4: 221-227

Morse, D., Choi, A.M., 2002. Heme oxygenase-1: the "emerging molecule" has arrived. Am J Respir Cell Mol Biol 27: 8-16
Nath, K.A., Grande, J.P, Haggard, J.J., Croatt, A.J., Katusic, Z.S., Solovey, A., Hebbel, R.P., 2001. Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease. Am J Pathol 158: 893-903
Nath, K.A., Haggard, J.J., Croatt, A.J., Grande, J.P., Poss, K.D., Alam, J., 2000. The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo. Am J Pathol 156: 1527-1535
Nath, K.A., Balla, G., Vercellotti, G.M., Balla, J., Jacob, H.S., Levitt, M.D., Rosenberg, M.E., 1992. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 90: 267-270
Nakamura, A., Suzuki, T., Kohsaka, T., 1995. Renal tubular function modulates urinary levels of Interleukin-6. Nephron 70: 416–420
Nolin, L., Courteau, M., 1999. Management of IgA nephropathy: evidence-based recommendations. Kidney Int 70: S56-62
Norman, J.T., Clark, I.M., Garcia, P.L., 2000. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 58: 2351-2366
Otterbein, L.E., Choi, A.M., 2000. Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279: L1029-1037
Pardo, A., Gibson, K., Cisneros, J., Richards, T.J., Yang, Y., Becerril, C., Yousem, S., Herrera, I., Ruiz, V., Selman, M., Kaminski, N., 2005. Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. Plos Med 2: e251
Papayianni, A., 1996. Cytokines, growth factors, and other inflammatory mediators in glomerulonephritis. Renal Failure 18:725-740
Page, E.L., 2002. Induction of hypoxia-inducible factor-1α by transcriptional and translational mechanisms. J Biol Chem 277: 48403–48409
Panzer, U., Thaiss, F., Zahner, G., Barth, P., Reszka, M., Reinking, R.R., Wolf, G., Helmchen, U., Stahl, R.A., 2001. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int 59: 1762-1769
Pichler, R.H., Franceschini, N., Young, B.A., Hugo, C., Andoh, T.F., Burdmann, E.A., Shankland, S.J., Alpers, C.E., Bennett, W.M., Couser, W.G., et al., 1995. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol 6: 1186-1196
Radeke, H.H., Resch, K., 1992. The inflammatory function of renal glomerular mesangial cells and their interaction with the cellular immune system. Clin Investig 70: 825-842
Rastaldi, M.P., Ferrario, F., Crippa, A., 2000. Glomerular monocyte-macrophage features in ANCA-positive renal vasculitis and cryoglobulinemic nephritis. J Am Soc Nephrol 11: 2036–2043
Risau, W., 1997. Mechanisms of angiogenesis. Nature 386: 671–674
Rovin, B.H., Dickerson, J.A., Tan, L.C., Hebert, C.A., 1995. Activation of nuclear factor-kappa B correlates with MCP-1 expression by human mesangial cells. Kidney Int 48: 1263–1271
Segerer, S., Kretzler, M., Strutz. F., 2007. Mechanisms of tissue injury and repair in renal diseases. In: Schrier R (ed). Diseases of the Kidney and Urinary Tract. Lippincott, Philadelphia
Shimizu, H., Takahashi, T., Suzuki, T., Yamasaki, A., Fujiwara, T., Odaka, Y., Hirakawa, M., Fujita, H., Akagi. R., 2000. Protective effect of heme oxygenase induction in ischemic acute renal failure. Crit Care Med 28: 809-817
Shiraishi, F., Curtis, L.M., Truong, L., Poss, K., Visner, G.A., Madsen, K., Nick, H.S., Agarwal, A., 2000. Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Am J Physiol Renal Physiol 278: F726-F736
Shihab, F.S., 2002. Angiotensin II regulation of vascular endothelial growth factor and receptors Flt-1 and KDR/Flk-1 in cyclosporine nephrotoxicity. Kidney Int 62: 422–433
Singh, R.P., Patarca, R., Schwartz, J., Singh, P., Cantor, H., 1990. Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo. J Exp Med 171: 1931-1942
Stafford, N.P., Pink, A.E., White, A.E., Glenn, J.R., Heptinstall, S., 2003. Mechanisms involved in adenosine triphosphate--induced platelet aggregation in whole blood. Arterioscler Thromb Vasc Biol 23: 1928-1933
Stahl, R.A., Thaiss, F., Haberstroh, U., Kahf, S., Shaw, A., Schoeppe, W., 1990. Cyclooxygenase inhibition enhances rat interleukin 1 beta-induced growth of rat mesangial cells in culture. Am J Physiol 259: F419-424
Su, B., Karin, M., 1996. Mitogen activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol 8: 402–411
Thomas, S.E., Lombardi, D., Giachelli, C., Bohle, A., Johnson, R.J., 1998. Osteopontin expression, tubulointerstitial disease, and essential hypertension. Am J Hypertens 11: 954-961
Taal, M.W., Zandi-Nejad, K., Weening, B., Shahsafaei, A., Kato, S., Lee, K.W., Ziai, F., Jiang, T., Brenner, B.M., MacKenzie, H.S., 2000. Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney. Kidney Int 58: 1664-1676
Takahashi, T., Morita, K., Akagi, R., Sassa, S., 2004. Heme oxygenase-1: a novel therapeutic target in oxidative tissue injuries. Curr Med Chem 11: 1545-1561
Trachtman, H., Futterweit, S., Singhal, P.C., Sankaran, R., Franki, N., 1996. Renal tubular epithelial cell-E. coli interaction products stimulate nitric oxide production in cultured rat renal medullary interstitial and mesangial cells. Res Commun Mol Pathol Pharmacol 94: 227–238
Tsai, T.J., Lin, R.H., Chang, C.C., Chen, Y.M., Chen, C.F., Ko, F.N., Teng, C.M., 1995. Vasodilator agents modulate rat glomerular mesangial cell growth and collagen synthesis. Nephron 70: 91-99
Tsukinoki, T., Sugiyama, H., Sunami, R., Kobayashi, M., Onoda, T., Maeshima, Y., Yamasaki, Y., Makino, H., 2004. Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-kappaB- mediated expression in cultured human mesangial cells. Clin Exp Nephrol 8: 196-205
Ushio-Fukai, M., 1999. Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem 274: 22699–22704
Veis, J.H., 1993. An overview of mesangial cell biology. Contrib Nephrol 104: 115-126
Vijayakrishnan, L., Rudra, S., Eapen, M.S., Dastidar, S., Ray, A., 2007. Small-molecule inhibitors of PDE-IV and -VII in the treatment of respiratory diseases and chronic inflammation. Expert Opin Investig Drugs 16: 1585-1599
Vogt, B.A., Shanley, T.P., Croatt, A., Alam, J., Johnson, K.J., Nath, K.A., 1996. Glomerular inflammation induces resistance to tubular injury in the rat. A novel form of acquired, heme oxygenase-dependent resistance to renal injury. J Clin Invest 98: 2139-2145
Wang, Y, Rangan, G. K., Goodwin, B., Tay Y.C., Wang, Y., Harris, C.H., 2000. Lipopolysaccharide-induced MCP-1 gene expression in rat tubular epithelial cells is nuclear factor- B dependent. Kidney Int 57: 2011–2022
Weyrich, A.S., Denis, M.M., Luhlmann-Eyre, J.R., 2005. Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation 111: 632-642
Wiggins, K.J., Tiauw, V., Zhang, Y., Gilbert, R.E., Langham, R.G., Kelly, D.J., 2008. Perindopril attenuates tubular hypoxia and inflammation in an experimental model of diabetic nephropathy in transgenic Ren-2 rats. Nephrology 13(8):721-729
Williams, B., 1998. A potential role for angiotensin II-induced vascular endothelial growth factor expression in the pathogenesis of diabetic nephropathy. Miner Electrolyte Metab. 24: 400–405
Wolf, G., 1998. Angiotensin II is involved in the progression of renal disease: implication of non-hemodynamic mechanisms. Nephrologie 19: 451–456
Xie, Y., Sakatsume, M., Nishi, S., Narita, I., Arakawa, M., Gejyo, F., 2001. Expression, roles, receptors, and regulation of osteopontin in the kidney. Kidney Int 60: 1645-1657
Yoo, K.H., Thornhill, B.A., Forbes, M.S., Coleman, C.M., Marcinko, E.S., Liaw, L., Chevalier, R.L., 2006. Osteopontin regulates renal apoptosis and interstitial fibrosis in neonatal chronic unilateral ureteral obstruction. Kidney Int 70: 1735-1741
Young, B.A., Burdmann, E.A., Johnson, R.J., Alpers, C.E., Giachelli, C.M., Eng, E., Andoh, T., Bennett, W.M., Couser, W.G., 1995. Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int 48: 439-448
Zatz, R., 2002. Mechanisms of progressive renal disease: role of angiotensin II, cyclooxygenase products and nitric oxide. J Hypertens 20: S37–S44
Zhou, Z., Song, R., Fattman, C.L., Greenhill, S., Alber, S., Oury, T.D., Choi, A.M., Morse, D., 2005. Carbon monoxide suppresses bleomycin-induced lung fibrosis. Am J Pathol 166: 27-37
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